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Heart failure with preserved ejection fraction (HFpEF) represents a prototypical cardiovascular condition in which machine learning may improve targeted therapies and mechanistic understanding of pathogenesis. Machine learning, which involves algorithms that learn from data, has the potential to guide precision medicine approaches for complex clinical syndromes such as HFpEF. It is therefore important to understand the potential utility and common pitfalls of machine learning so that it can be applied and interpreted appropriately. Although machine learning holds considerable promise for HFpEF, it is subject to several potential pitfalls, which are important factors to consider when interpreting machine learning studies.

Many cancers carry recurrent, change-of-function mutations affecting RNA splicing factors. Here, we describe a method to harness this abnormal splicing activity to drive splicing factor mutation-dependent gene expression to selectively eliminate tumor cells. We engineered synthetic introns that were efficiently spliced in cancer cells bearing SF3B1 mutations, but unspliced in otherwise isogenic wild-type cells, to yield mutation-dependent protein production. A massively parallel screen of 8,878 introns delineated ideal intronic size and mapped elements underlying mutation-dependent splicing. Synthetic introns enabled mutation-dependent expression of herpes simplex virus-thymidine kinase (HSV-TK) and subsequent ganciclovir (GCV)-mediated killing of SF3B1-mutant leukemia, breast cancer, uveal melanoma and pancreatic cancer cells in vitro, while leaving wild-type cells unaffected. Delivery of synthetic intron-containing HSV-TK constructs to leukemia, breast cancer and uveal melanoma cells and GCV treatment in vivo significantly suppressed the growth of these otherwise lethal xenografts and improved mouse host survival. Synthetic introns provide a means to exploit tumor-specific changes in RNA splicing for cancer gene therapy.

Objectives This study aimed to investigate mitral annular dynamics in atrial fibrillation (AF) and after sinus rhythm restoration, and to assess the relationship between annular dynamics and mitral regurgitation (MR). Background AF can be associated with MR that improves after sinus rhythm restoration. Mechanisms underlying this atrial functional MR (AFMR) are ill-understood and generally attributed to left atrial remodeling. Methods Fifty-three patients with persistent AF and normal left ventricular ejection fraction were prospectively examined by means of 3-dimensional transesophageal echocardiography before, immediately after, and 6 weeks after electric cardioversion to sinus rhythm. Annular motion was assessed during AF and in sinus rhythm with the use of 3-dimensional analysis software, and the relationship with MR severity was explored. Results During AF and immediately after sinus rhythm restoration, the mitral annulus behaved relatively adynamically, with an overall change in annular area of 10.3% (95% CI: 8.7%-11.8%) and 12.2% (95% CI: 10.6%-13.8%), respectively. At follow-up, a significant increase in annular dynamics (19.0%; 95% CI: 17.4%-20.6%; P Conclusions Mitral annular dynamics are impaired in AF, with blunted presystolic narrowing that contributes to AFMR. Sinus rhythm restoration allows gradual recovery of presystolic annular dynamics. Improved annular dynamics decrease AFMR severity by optimizing annular-leaflet imbalance, regardless of LA remodeling.

BACKGROUND Pulmonary thromboendarterectomy (PTE) is a curative procedure for chronic thromboembolic pulmonary hypertension (CTEPH). Right ventricular free wall strain (RV FWS) and right atrial strain (RAS) are not well studied in a CTEPH population. We sought to determine temporal trends in RAS and RV FWS in patients post-PTE. METHODS 28 patients undergoing PTE for CTEPH were prospectively enrolled in a surgical database. Comprehensive echocardiographic assessment of the right heart was performed including RV FWS, right atrial volume, and the three components of RAS: reservoir, conduit, and booster strain. RESULTS Patients undergoing PTE demonstrated improvement in NYHA functional class (P

CRISPR-based cancer dependency maps are accelerating advances in cancer precision medicine, but adequate functional maps are limited to the most common oncogenes. To identify opportunities for therapeutic intervention in other rarer subsets of cancer, we investigate the oncogene-specific dependencies conferred by the lung cancer oncogene, RIT1. Here, genome-wide CRISPR screening in KRAS, EGFR, and RIT1-mutant isogenic lung cancer cells identifies shared and unique vulnerabilities of each oncogene. Combining this genetic data with small-molecule sensitivity profiling, we identify a unique vulnerability of RIT1-mutant cells to loss of spindle assembly checkpoint regulators. Oncogenic RIT1M90I weakens the spindle assembly checkpoint and perturbs mitotic timing, resulting in sensitivity to Aurora A inhibition. In addition, we observe synergy between mutant RIT1 and activation of YAP1 in multiple models and frequent nuclear overexpression of YAP1 in human primary RIT1-mutant lung tumors. These results provide a genome-wide atlas of oncogenic RIT1 functional interactions and identify components of the RAS pathway, spindle assembly checkpoint, and Hippo/YAP1 network as candidate therapeutic targets in RIT1-mutant lung cancer., RIT1 mutations are mutually exclusive with other lung cancer drivers and lack targeted therapies. Here the authors examine genetic dependencies of mutant RIT1 with genome-wide CRISPR screens, revealing synergy between RIT1 and YAP1, and increased sensitivity to Aurora kinase inhibitors.

BACKGROUND: PVDOMICS (Pulmonary Vascular Disease Phenomics) is a precision medicine initiative to characterize pulmonary vascular disease (PVD) using deep phenotyping. PVDOMICS tests the hypothesis that integration of clinical metrics with omic measures will enhance understanding of PVD and facilitate an updated PVD classification. OBJECTIVES: The purpose of this study was to describe clinical characteristics and transplant-free survival in the PVDOMICS cohort. METHODS: Subjects with World Symposium Pulmonary Hypertension (WSPH) group 1–5 PH, disease comparators with similar underlying diseases and mild or no PH and healthy control subjects enrolled in a cross-sectional study. PH groups, comparators were compared using standard statistical tests including log-rank tests for comparing time to transplant or death. RESULTS: A total of 1,193 subjects were included. Multiple WSPH groups were identified in 38.9% of PH subjects. Nocturnal desaturation was more frequently observed in groups 1, 3, and 4 PH vs comparators. A total of 50.2% of group 1 PH subjects had ground glass opacities on chest computed tomography. Diffusing capacity for carbon monoxide was significantly lower in groups 1–3 PH than their respective comparators. Right atrial volume index was higher in WSPH groups 1–4 than comparators. A total of 110 participants had a mean pulmonary artery pressure of 21–24 mm Hg. Transplant-free survival was poorest in group 3 PH. CONCLUSIONS: PVDOMICS enrolled subjects across the spectrum of PVD, including mild and mixed etiology PH. Novel findings include low diffusing capacity for carbon monoxide and enlarged right atrial volume index as shared features of groups 1–3 and 1–4 PH, respectively; unexpected, frequent presence of ground glass opacities on computed tomography; and sleep alterations in group 1 PH, and poorest survival in group 3 PH. PVDOMICS will facilitate a new understanding of PVD and refine the current PVD classification. (Pulmonary Vascular Disease Phenomics Program PVDOMICS [PVDOMICS]; NCT02980887)

PurposeGrounded in hydrodynamic theory, proximal isovelocity surface area (PISA) is a simplistic and practical technique widely used to quantify valvular regurgitation flow. PISA provides a relatively reasonable, though slightly underestimated flow rate for circular orifices. However, for elliptical orifices frequently seen in functional mitral regurgitation, PISA underestimates the flow rate. Based on data obtained with computational fluid dynamics (CFD) and in vitro experiments using systematically varied orifice parameters, we hypothesized that flow rate underestimation for elliptical orifices by PISA is predictable and within a clinically acceptable range.MethodsWe performed 45 CFD simulations with varying orifice areas 0.1, 0.3 and 0.5 cm2, orifice aspect ratios 1:1, 2:1, 3:1, 5:1, and 10:1, and peak velocities (Vmax) 400, 500 and 600 cm/s. The ratio of computed effective regurgitant orifice area to true effective area (EROAC/EROA) against the ratio of aliasing velocity to peak velocity (VA/Vmax) was analyzed for orifice shape impact. Validation was conducted with in vitro imaging in round and 3:1 elliptical orifices.ResultsPlotting EROAC/EROA against VA/Vmax revealed marginal flow underestimation with 2:1 and 3:1 elliptical axis ratios against a circular orifice (A/Vmax), rising to ≤35% for 10:1 ratio. In vitro modeling confirmed CFD findings; there was a 8.3% elliptical EROA underestimation compared to the circular orifice estimate.ConclusionPISA quantification for regurgitant flow through elliptical orifices produces predictable, but generally small, underestimation deemed clinically acceptable for most regurgitant orifices.

Grounded in hydrodynamic theory, proximal isovelocity surface area (PISA) is a simplistic and practical technique widely used to quantify valvular regurgitation flow. PISA provides a relatively reasonable, though slightly underestimated flow rate for circular orifices. However, for elliptical orifices frequently seen in functional mitral regurgitation, PISA underestimates the flow rate. Based on data obtained with computational fluid dynamics (CFD) and in vitro experiments using systematically varied orifice parameters, we hypothesized that flow rate underestimation for elliptical orifices by PISA is predictable and within a clinically acceptable range. We performed 45 CFD simulations with varying orifice areas 0.1, 0.3 and 0.5 cm

Aims There is a wide spectrum of diseases associated with pulmonary hypertension, pulmonary vascular remodelling, and right ventricular dysfunction. The NIH-sponsored PVDOMICS network seeks to perform comprehensive clinical phenotyping and endophenotyping across these disorders to further evaluate and define pulmonary vascular disease. Methods and results Echocardiography represents the primary non-invasive method to phenotype cardiac anatomy, function, and haemodynamics in these complex patients. However, comprehensive right heart evaluation requires the use of multiple echocardiographic parameters and optimized techniques to ensure optimal image acquisition. The PVDOMICS echo protocol outlines the best practice approach to echo phenotypic assessment of the right heart/pulmonary artery unit. Conclusion Novel workflow processes, methods for quality control, data for feasibility of measurements, and reproducibility of right heart parameters derived from this study provide a benchmark frame of reference. Lessons learned from this protocol will serve as a best practice guide for echocardiographic image acquisition and analysis across the spectrum of right heart/pulmonary vascular disease.

OBJECTIVE: While American and European consensus statements advocate employing the ratio of the transmitral E velocity and tissue Doppler early diastolic mitral annular velocity (E/e’) in the assessment of left heart filling pressures, recent reports have questioned the reliability of this ratio to predict left atrial pressures in a variety of disease states. We hypothesized that there is a clinically significant correlation between E/e’ and pulmonary capillary wedge pressure (PCWP) in patients with severe aortic stenosis. DESIGN: Retrospective cohort study PARTICIPANTS: 733 consecutive patients with severe aortic stenosis who underwent Transcatheter Aortic Valve Replacement (TAVR) for severe aortic stenosis INTERVENTIONS: None MEASUREMENTS AND MAIN RESULTS: PCWP and E/e’(ave) (average of the lateral and medial annulus tissue Doppler velocities) were measured using pulmonary artery catheter and transthoracic echocardiography during pre-procedural evaluation. Patients were grouped by left ventricular ejection fraction (LVEF) ≥ 50% and LVEF < 50%. Spearman rank correlation, anova, t-tests and chi squared tests were used to analyze the data. 79 patients met the inclusion criteria. There was no significant correlation between E/e’(ave) and PCWP (n=79, spearman, r=0.096 p=0.3994). This correlation did not improve when ventricular function was considered (LVEF < 50%: n=11, spearman, r=−0.097, p=0.776; LVEF≥ 50%: n=68, spearman, r=0.116, p=0.345). There was no statistically significant difference in mean PCWP between each range of E/e’(ave). CONCLUSION: We did not find a clinically relevant relationship between E/e’ and PCWP in patients with severe aortic stenosis.

OBJECTIVES This study was conducted to determine if gender bias explains the worse outcomes in women than in men who undergo mitral valve surgery for degenerative mitral regurgitation. METHODS Patients who underwent mitral valve surgery for degenerative mitral regurgitation with or without concomitant ablation surgery for atrial fibrillation were identified from the Cardiovascular Research Database of the Clinical Trial Unit of the Bluhm Cardiovascular Institute at Northwestern Memorial Hospital and were defined according to the Society of Thoracic Surgery National Adult Cardiac Surgery Database. Of the 1004 patients (33% female, mean age 62.1 ± 12.4 years; 67% male, mean age 60.1 ± 12.4 years) who met this criteria, propensity score matching was utilized to compare sex-related differences. RESULTS Propensity score matching of 540 patients (270 females, mean age 61.0 ± 12.2; 270 males, mean age 60.9 ± 12.3) demonstrated that 98% of mitral valve surgery performed in both groups was mitral valve repair and 2% was mitral valve replacement. Preoperative CHA2DS2-VASc scores were higher in women and fewer women were discharged directly to their homes. Before surgery, women had smaller left heart chambers, lower cardiac outputs, higher diastolic filling pressures and higher volume responsiveness than men. However, preoperative left ventricular and right ventricular strain values, which are normally higher in women, were similar in the 2 groups, indicating worse global strain in women prior to surgery. CONCLUSIONS The worse outcomes reported in women compared to men undergoing surgery for degenerative mitral regurgitation are misleading and not based on gender bias except in terms of referral patterns. Men and women who present with the same type and degree of mitral valve disease and similar comorbidities receive the same types of surgical procedures and experience similar postoperative outcomes. Speckle-tracking echocardiography to assess global longitudinal strain of the left and right ventricles should be utilized to monitor for myocardial dysfunction related to chronic mitral regurgitation.

Immune checkpoint blockade therapy has revolutionized cancer care, including the treatment of advanced metastatic disease. However, most patients derive little or no clinical benefit from these therapies and many cancer types are notoriously non-responsive. Motivated by (1) the correlation between tumor neoantigen abundance and anti-tumor immunity and (2) that most cancers are characterized by widespread dysregulation of RNA processing, we reasoned that pharmacologic modulation of RNA splicing might increase cancer cell immunogenicity via the generation of splicing-derived neoantigens. We demonstrated that two compounds which modulate RNA splicing via distinct mechanisms, inhibited tumor growth and enhanced response to immune checkpoint blockade in a manner dependent on host T cells and peptides presented on tumor MHC class I. Critical for their clinical translatability, therapeutic doses of splicing inhibitors were non-toxic, tolerated by the host immune system, and did not affect T cell activation, proliferation, and anti-cancer killing activities. Mechanistically, splicing modulation induced stereotyped, dose-dependent “splicing failure” — dramatic intron retention, alternative exon skipping, etc. — that was consistent across multiple mouse and human tumor types. By combining RNA-seq-based peptide predictions and mass spectrometry of the MHC I-bound immunopeptidome, we identified drug-induced, splicing-derived peptides that promote the expansion of antigen-specific CD8+ T cells and trigger anti-tumor T cell responses in vivo. These data definitively identify splicing modulation as an untapped source of immunogenic peptides and provide a means to enhance response to checkpoint blockade that is readily translatable to the clinic. Citation Format: James D. Thomas, Sydney X. Lu, Emma De Neef, Erich Sabio, Benoit Rousseau, Mathieu Gigoux, David A. Knorr, Benjamin Greenbaum, Yuval Elhanati, Simon J. Hogg, Andrew Chow, Arnab Ghosh, Abigail Xie, Dmitriy Zamarin, Daniel Cui, Caroline Erickson, Michael Singer, Hana Cho, Eric Wang, Bin Lu, Benjamin H. Durham, Harshal Shah, Diego Chowell, Austin M. Gabel, Yudao Shen, Jing Liu, Jian Jin, Matthew C. Rhodes, Richard E. Taylor, Henrik Molina, Jedd D. Wolchok, Taha Merghoub, Luis A. Diaz Jr, Omar Abdel-Wahab, Robert K. Bradley. Pharmacologic modulation of RNA splicing enhances anti-tumor immunity. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5742.

We present the novel use of a deep learning–derived technology trained on the skilled hand movements of cardiac sonographers that guides novice users to acquire high-quality bedside cardiac ultrasound images. We illustrate its use at the point of care through a series of patient encounters in the COVID-19 intensive care unit. (Level of Difficulty: Beginner.), Graphical abstract

Graphical abstract, Highlights • Angle correction may be needed when PISA is applied to a near commissural MR jet. • Four-dimensional flow MRI enabled MR volume quantification with 3D jet visualization. • Exercise-induced VT may have complex structural, genetic, and ECG etiologies.

Tricuspid valve (TV) degeneration after surgical repair with an annuloplasty ring is problematic as redo operation carries high mortality. This can be addressed with transcatheter therapies to implant a valve within in prior ring (tricuspid valve-in-ring). When an incomplete ring is present, paravalvular leak is commonly encountered after tricuspid valve-in-ring (TViR) implant; however, this can be addressed with paravalvular leak closure devices. Multimodality imaging including cardiac computed tomography and three-dimensional (3D) transesophageal echocardiography (TEE) are important for successful TViR implant. We report a case of tricuspid regurgitation after tricuspid repair with an incomplete annuloplasty ring and subsequent paravalvular leak closure.

While RNA-seq has enabled comprehensive quantification of alternative splicing, no correspondingly high-throughput assay exists for functionally interrogating individual isoforms. We describe pgFARM (paired guide RNAs for alternative exon removal), a CRISPR–Cas9-based method to manipulate isoforms independent of gene inactivation. This approach enabled rapid suppression of exon recognition in polyclonal settings to identify functional roles for individual exons, such as an SMNDC1 cassette exon that regulates pan-cancer intron retention. We generalized this method to a pooled screen to measure the functional relevance of ‘poison’ cassette exons, which disrupt their host genes’ reading frames yet are frequently ultraconserved. Many poison exons were essential for the growth of both cultured cells and lung adenocarcinoma xenografts, while a subset had clinically relevant tumor-suppressor activity. The essentiality and cancer relevance of poison exons are likely to contribute to their unusually high conservation and contrast with the dispensability of other ultraconserved elements for viability. pgFARM (paired guide RNAs for alternative exon removal) is a CRISPR–Cas9-based approach to manipulate alternative splicing and identify functional roles for individual exons, including poison exons with essential and tumor-suppressor roles.

PURPOSE: This study investigated the impact of bicuspid aortic valve (BAV) on valve morphology and motion as well as proximal and aortic hemodynamics using a same-day echocardiography and cardiac MRI. METHODS: Transthoracic echocardiography, two-dimensional cine MRI of the aortic valve, and aortic 4D flow MRI were performed on the same day in 9 normofunctional BAV patients (age=41±12, 3 female), 4 BAV with moderate to severe aortic stenosis (AS) (age=63±5, 1 female), and 36 healthy tricuspid aortic valve controls (age=52±10, 21 female). Valve opening and closing timings and transvalvular peak velocity were measured using B-mode and Doppler echocardiogram, respectively. Valve orifice morphology at fully-opened state was characterized using cine MRI. Ascending aortic (AAo) wall shear stress (WSS) was measured using 4D flow MRI data. RESULTS: Valve motion timings were similar between BAV and controls. BAV was associated with increased orifice aspect ratio (1.44±0.11 vs. 1.10±0.13, PCONCLUSION: A same-day echo and MRI imaging allows for comprehensive assessment of the impact of aortic valve disease on valve function and hemodynamics. In this pilot application to BAV, we found increased orifice aspect ratio may be responsible for increased transvalvular peak velocity and maximum AAo WSS.

Cardiomyopathy is a general term used to describe a heterogeneous group of diseases that result in impairment of ventricular function. Clinical manifestations of these diseases can range from an asymptomatic state to heart failure or arrhythmias to sudden cardiac death. Cardiac imaging, in particular echocardiography, plays a vital role in the diagnosis and management of affected individuals, and recently strain imaging has garnered great interest due to its superior ability to identify early functional abnormalities. This chapter focuses on the most common cardiomyopathies and will focus on longitudinal strain (LS) in the affected chamber; for most, this means left ventricular LS with the exception of arrhythmogenic right ventricular cardiomyopathy.

Introduction: Myocardial strain imaging provides a complex dataset that is often reduced to a single parameter, global longitudinal peak strain (GLPS). Raw temporal strain data is largely unexplored and restricted as studies often only save images of graphs lacking numerical data. While certain strain imaging packages do allow for the prospective export of raw data, the task is slow, rarely done, and cannot be done retrospectively. The troves of retrospective strain studies saved as images can be unlocked by reconstructing the numerical values contained in strain graphs. Such a dataset would be critical to future artificial intelligence strain analysis and morphological detection of disease modalities. This study aims to investigate the methods of extracting and reconstructing strain curve graphs to raw numerical outputs. Methods: By using vendor-specific color recognition algorithms, individual curves can be isolated as scattergram type plots of pixels. These pixel locations are converted to temporal strain values by defining scale factors for the graph. Intelligence-guided filtering, interpolation, and curve overlap filling can convert the pixel scattergrams into clean and complete temporal strain data. Using a set of 21 studies each containing 3 views (2Ch, 4Ch, APLAx) with each view containing 6 regional curves, 378 unique curves were reconstructed and compared to prospectively exported temporal strain data. Results: Results demonstrate that this method reconstructs the numerical data with high accuracy and precision. The reconstructed data was compared with the exported numerical data, yielding an average R 2 of .996 with an average runtime per study of 7.32s. The minute deviation from fidelity can be attributed to the finite resolution of the pixels in the analyzed graph. Discussion: Highly accurate temporal data can be extracted from routine strain graphs in clinical studies, which may allow for more nuanced assessment and deep learning of strain.

This study aims to systematically verify if the simplified geometry and flow profile of the left ventricular outflow tract (LVOT) assumed in 2D echocardiography is appropriate while examining the utility of 4D flow MRI to assess valvular disease. This prospective study obtained same-day Doppler echocardiography and 4D flow MRI in 37 healthy volunteers (age: 51.9 ± 18.2, 20 females) and 7 aortic stenosis (AS) patients (age: 64.2 ± 9.6, 1 female). Two critical assumptions made in echocardiography for aortic valve area assessment were examined, i.e. the assumption of (1) a circular LVOT shape and (2) a flat velocity profile through the LVOT. 3D velocity and shape information obtained with 4D flow MRI was used as comparison. It was found that the LVOT area was lower (by 26.5% and 24.5%) and the velocity time integral (VTI) was higher (by 28.5% and 30.2%) with echo in the healthy and AS group, respectively. These competing errors largely cancelled out when examining individual and cohort averaged LVOT stroke volume. The LVOT area, VTI and stroke volume measured by echo and 4D flow MRI were 3.6 ± 0.7 vs. 4.9 ± 1.0 cm

PURPOSE The purpose of this study was to evaluate the accuracy of four-dimensional (4D) flow MRI for direct assessment of peak velocity, flow volume, and momentum of a mitral regurgitation (MR) flow jets using an in vitro pulsatile jet flow phantom. We systematically investigated the impact of spatial resolution and quantification location along the jet on flow quantities with Doppler ultrasound as a reference for peak velocity. METHODS Four-dimensional flow MRI data of a pulsatile jet through a circular, elliptical, and 3D-printed patient-specific MR orifice model was acquired with varying spatial resolution (1.5-5 mm isotropic voxel). Flow rate and momentum of the jet were quantified at various axial distances (x = 0-50 mm) and integrated over time to calculate Voljet and MTIjet . In vivo assessment of Voljet and MTIjet was performed on 3 MR patients. RESULTS Peak velocities were comparable to Doppler ultrasound (3% error, 1.5 mm voxel), but underestimated with decreasing spatial resolution (-40% error, 5 mm voxel). Voljet was similar to regurgitant volume (RVol) within 5 mm, and then increased linearly with the axial distance (19%/cm) because of flow entrainment. MTIjet remained steady throughout the jet (2%/cm) as theoretically predicted. Four and 9 voxels across the jet were required to measure flow volume and momentum-time-integral within 10% error, respectively. CONCLUSION Four-dimensional flow MRI detected accurate peak velocity, flow rate, and momentum for in vitro MR-mimicking flow jets. Spatial resolution significantly impacted flow quantitation, which otherwise followed predictions of flow entrainment and momentum conservation. This study provides important preliminary information for accurate in vivo MR assessment using 4D flow MRI.

To determine the prevalence of concomitant aortic regurgitation (AR) in cardiac surgery and the outcomes of treatment options.Between April 2004 and June 2018, 3289 patients underwent coronary artery bypass, mitral valve, or aortic aneurysm surgery without aortic stenosis. AR was graded none/trivial (score = 0), mild (score = 1+), or moderate (score = 2+). Patients with untreated 2+ AR were compared with those with 0 or 1+ AR, and to those with 2+ AR who had aortic valve surgery. Thirty-day and late survival, echocardiography, and clinical outcomes were compared using propensity score matching.One hundred thirty-eight patients (4.2%) had 2+ AR; and 45 (33%) received aortic valve repair (n = 9) or replacement (n = 36) in the treated group and were compared with 2765 untreated patients with 0 AR and 386 patients with 1+ AR. Valve surgery was more common with anatomic leaflet abnormalities: bicuspid aortic valve (9% vs 0%; P lt; .01), rheumatic valve disease (16% vs 3%; P lt; .01), and calcification (47% vs 27%; P = .021). In unadjusted analysis, lower preoperative AR grade was associated with increased 10-year survival (P lt; .001). At year 10, progression to more-than-moderate AR among moderate AR patients was 2.6% and late intervention rate was 3.1%. In the untreated 2+ AR group, on last follow-up echocardiogram, 58% had improvement in AR, 41% remained 2+, and only 1% progressed to severe AR.Aortic valve surgery in select patients with concomitant moderate AR can be added with minimal added risk, but untreated AR does not influence long-term survival after cardiac surgery and rarely required late intervention.